Throughout this application various publications are referred to in parentheses. Full citations for these references may be found at the end of the specification. The disclosures of these publications are hereby incorporated by reference in their entirety into the subject application to more fully describe the art to which the subject invention pertains.
Multiple members of the family Filoviridae of enveloped negative-strand RNA viruses (filoviruses) cause a highly lethal hemorrhagic fever for which no approved treatments are available. While Ebola virus (EBOV) is responsible for the ongoing unprecedented epidemic in West Africa, the antigenically-distinct Sudan virus (SUDV), Bundibugyo virus (BDBV), Marburg virus (MARV), and Ravn virus (RAVV) have also caused outbreaks with high case fatality rates (30-90%). Moreover, novel filoviruses with zoonotic potential likely await discovery in the filovirus-endemic zone of equatorial Africa and elsewhere. As a case in point, the founding member of a distinct Filovirus clade, Lloviu virus (LLOV), was recently isolated in southern Spain and Portugal, where it is suspected to have caused mass die-offs of insectivorous cave bats (Negredo, PLoS Pathog, 2011).
The current outbreak in West Africa has seen ZMapp (Mapp Biopharmaceuticals), a mixture of three humanized mouse monoclonal antibodies (mAbs) against the EBOV spike glycoprotein (GP), emerge as a promising treatment for Ebola virus disease. More generally, it has provided a powerful proof-of-concept for mAb-based prophylactics and therapeutics against filoviruses. However, a major limitation of ZMapp and other planned mAb cocktails is their narrow spectrum of action (against EBOV only), dictated by the high antigenic diversity of filovirus GP proteins. Because the development, stockpiling, and deployment of separate mAb cocktails against each virulent filovirus is impractical, broad-spectrum mAb-based treatments that target multiple filoviruses are highly desirable.
The endo/lysosomal cholesterol transporter Niemann-Pick C1 (NPC1) is a universal intracellular receptor for entry and infection by filoviruses, and is required for in vivo pathogenesis by both EBOV and MARV (and almost certainly by BDBV, SUDV, and RAVV as well) (Carette, Nature, 2011; Ng, Virology, 2014). NPC1 protein has a cytoplasmic C-terminus, 13 transmembrane domains, and 3 large loops in the lumen of the endosome (Davies et al., 2000). One complication in targeting NPC1 with monoclonal antibodies (mAbs) is its exclusive localization to late endosomal compartments, where it is protected from extracellular antibodies.
The present invention uses bispecific antibodies (bsAbs) with potent anti-filovirus activity to address the need for methods for treating subjects infected with filoviruses or who are at risk for infection with filoviruses.